Early detection and withdrawal of the causative drug is the single most important step in the management of adverse hepatic reaction.
MANAGEMENT OF IDIOSYNCRATIC
HEPATOTOXICITY
Early
detection and withdrawal of the causative drug is the single most important
step in the management of adverse hepatic reaction. Cases of serious and often
fatal hepatotoxicity due to isoniazid, halothane, valproate, nitrofurantoin and
perhexiline are often linked to continuation or resumption of the drug
following symptoms that could have been attributable to drug-induced liver
reaction (Farrell, 1994; Lo et al.,
1998; Moulding, 1999). The Seattle-King County Public Health Department used a
protocol to monitor isoniazid therapy, which included advising the patient at
each visit to stop the medication and call the clinic if symptoms of
hepatotoxicity occurred. With care-ful monitoring, the rate of hepatotoxicity
in 11 141 patients was much lower (0.1%–0.15%) than previ-ously reported (1%),
and there were no deaths (Nolan, Goldberg and Buskin, 1999). Prompt withdrawal
of the drug is also important because the long-term prog-nosis may be worse if
the responsible agent is contin-ued. In a retrospective study, one-third of
patients with drug-induced liver disease had persistently abnormal liver tests
(liver enzymes and/or imaging) at median follow-up of 5 years, and the
detection of fibrosis in the liver biopsy and continued drug intake after the
initial liver injury predicted adverse outcome (Aithal and Day, 1999).
Management
of acute hepatic failure secondary to idiosyncratic hepatic reaction is similar
to that of viral hepatitis. The overall mortality of drug-induced hepatic
failure (excluding paracetamol over-dose) appears to be higher than that of
viral hepatitis. Despite the availability of liver transplantation, 13% of
those who develop jaundice due to severe hepa-totoxicity die, and in patients
with halothane-induced liver injury, the mortality rate of 40% have been
reported (Bjornsson and Olsson, 2005). Corticosteroid treatment has not been
shown to be beneficial in the management of drug-induced hepatitis. There is no
clear evidence that ursodeoxycholic acid therapy changes outcome in chronic
cholestasis.
Experience
gained by wide clinical usage of a drug following marketing may assist in
recognising indi-vidual risk factors and better definition of safe dosage.
Strategies of avoiding the prescription in ‘at-risk situ-ations’ and safer
dosage regimes have reduced adverse hepatic reactions due to several drugs.
Some such examples include the avoidance of reuse of halothane within 3 months,
parenteral administration of large doses of tetracycline as well as its use in
pregnancy and renal disease, aspirin in children and valproic acid in
combination therapy in children under the age of 3 years (Farrell, 1994;
Neuberger, 1998). The incidence of hepatic fibrosis with weekly low-dose
methotrexate regimes is much lower than that reported with daily dose regimes
(Boffa et al., 1995; Aithal et al., 2004a).
When
a new drug is recognised to be associated with significant hepatic ADR, it has
become common prac-tice to recommend regular monitoring of liver enzymes for
the early detection of liver injury so that drug can be withdrawn before
serious hepatotoxic reaction occurs. Although this is logical, the level of
enzyme elevation at which the risk of serious, progressive hepatotoxicity is significant
and yet the injury is completely reversible on the withdrawal of medication is
still uncertain (Kaplowitz, 2005). In addition, compliance with such
recommendation remains low (Gaham et al.,
2001).
Of
even greater importance in the determination of individual risk is the
inherited factors that affect the kinetics and dynamics of numerous drugs.
Suscepti-bility to hepatic drug reaction depends principally on genetic factors
that determine the metabolism, as well as the biochemical and immunological
responses, to the metabolites. A major difference between genetic and
environmental variation is that an inherited trait has to be tested for only
once in a lifetime, whereas environmental effects change continuously. In the
future, the discovery of pharmacogenetic traits will change with new
technologies based on genomics. Rapid sequencing and single-nucleotide
polymor-phisms (SNPs) will play a major role in the linking of sequence
variations with heritable phenotypes of drug response (Meyer, 2000). In fact,
pharmacoge-netics technology may enable a significantly better post-marketing
surveillance system. In this proposed concept (Roses, 2000), hundreds of
thousands of patients who receive the drug would have blood taken and stored in
an approved location. As rare, serious adverse events are documented, DNA from
patients who experienced the ADR could be compared with that from controls, who
did not have adverse reaction while on the drug. This would enable ‘genetic
finger-prints’ (SNP profiles) of the subjects susceptible to the adverse event
to be determined. These adverse event profiles would be combined with efficacy
profiles to produce a comprehensive medicine response profile. This would allow
the selection of patients for both efficacy and lower complications of drug
therapy.
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